Repositioning Tacrolimus: Evaluation of the Effect of Short-Term Tacrolimus Treatment on Osteoprogenitor Cells and Primary Cells for Bone Regenerative Engineering

Assay Drug Dev Technol. Feb/Mar 2019;17(2):77-88. doi: 10.1089/adt.2018.876. Epub 2019 Jan 9.

Abstract

Small-molecule-based bone regenerative engineering is an encouraging strategy for repair and regeneration of skeletal tissue. Using osteogenic small molecules for engineering bone tissue has several potential benefits over polypeptide-based approaches. Interestingly, hundreds of such small molecules possess the capability to promote osteogenesis, and several of these are already approved by the FDA for use in other applications, indicating their safety for human use. However, the need for their use at a high frequency and/or duration, due to their short half-life and nonspecificity, is still problematic. We, and others, have identified several non-FDA-approved small-molecule-based compounds that induce long-lasting osteogenic effects following short-term (<24 h) treatment. In this study, however, we have performed a proactive screen to investigate and compare the osteogenic effects of several preselected FDA-approved small-molecule drugs in vitro using osteoprogenitor MC3T3-E1 cells. Our results demonstrate that treatment with the small-molecule drug tacrolimus (FK-506) for 24 h significantly enhanced long-lasting osteogenic responses in both osteoprogenitor cells and primary cell cultures. In addition, we tested whether a short-term treatment with FK-506 is able to induce osteogenic differentiation of cells seeded on a polymeric scaffold in vitro. Using an osteogenic small molecule that has long-lasting effects despite a short duration of exposure to cells may alleviate the undesirable effects often seen with many osteogenic small molecules.

Keywords: bone regeneration; drug delivery; drug repositioning; regenerative engineering; small molecules; tacrolimus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Bone Regeneration / drug effects*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Humans
  • Immunosuppressive Agents / chemistry
  • Immunosuppressive Agents / pharmacology*
  • Mesenchymal Stem Cells / drug effects*
  • Mice
  • Molecular Structure
  • Osteogenesis / drug effects*
  • Regenerative Medicine
  • Structure-Activity Relationship
  • Tacrolimus / chemistry
  • Tacrolimus / pharmacology*
  • Tissue Engineering*

Substances

  • Immunosuppressive Agents
  • Tacrolimus